Hydroxy-methyl-glutaryl (HMG) CoA reductase inhibitors (statins) are the most effective medications for managing elevated concentrations of low-density lipoprotein cholesterol. Resultantly, they are the most prescribed drugs in the United States and the world. Data regarding the effects of statins on cognition are discrepant, although randomized clinical trials have shown either no effect of statins on cognition or even small cognitive performance deficits. In a small but growing number (~60) of reports, statins have even been associated with memory loss and/or dementia that often resolves with cessation of therapy. Recent evidence suggests that adverse cognitive outcomes associated with statin therapy are directly related to the potency of the statin, which is particularly relevant given that increasing numbers of adults are treated with high-doses of potent statins (i.e., 80 mg atorvastatin and simvastatin and 40mg rosuvastatin) and to date there have been no randomized clinical trials examining cognition with high-dose, potent statins in healthy adults. Accordingly, the purpose of the present proposal is to assess neuronal activation and cognition in adults treated with 80 mg atorvastatin for six months vs. placebo using subjects currently enrolled in the NHLBI-sponsored, randomized, double-blind clinical trial, The Effects of Statins On Skeletal Muscle Function (The STOMP Study;Thompson, PI). Neuronal activation will be measured by assessing the blood oxygen level dependent (BOLD) signal on fMRI during two different memory-based tasks while subjects are on study drug and (using alternate versions of tasks) two months after they have ceased treatment. Behavioral measures from these in-scanner tests will also be analyzed. Generalized cognitive tests will also be administered twice, in alternate versions, to assess cognitive test performance including different forms of memory. The hypothesis of the study is that adults treated with high dose atorvastatin will demonstrate altered patterns of neuronal activation when on-drug vs. off-drug in contrast to adults treated with placebo, as preliminary data from subjects in the STOMP study indicate that adults treated with atorvastatin exhibit reduced activation during the encoding phase and exaggerated activation during the recognition phase of two different memory tasks. The proposed study is important given the present widespread use of statins at high concentrations. Statins are lifesaving medications, but anecdotal evidence, case reports, and survey data indicate that statins may evoke adverse changes in memory and cognition in otherwise healthy adults. Understanding if and how a high-dose, potent statin affects cognitive function in healthy adults is critical to evaluate further the risk and benefit of these drugs and to design treatment strategies to reduce cardiovascular disease risk. Public Health Relevance: Hydroxy-methyl-glutaryl (HMG) CoA reductase inhibitors (statins) are the most prescribed drugs in the United States and the world for lowering cholesterol, but anecdotal evidence, case reports, and survey data indicate that high-dose, potent statins may evoke adverse changes in memory and cognition in otherwise healthy adults. The current proposal is designed to determine the effects of six months of high-dose atorvastatin therapy vs. placebo on neuronal activation and cognition in 150 healthy, statin-na[unreadable]ve adults currently enrolled in the NHLBI-sponsored, randomized, double-blind clinical trial, The Effects of Statins On Skeletal Muscle Function (P.D. Thompson, PI). Understanding if and how a high-dose, potent statin affects cognitive function in healthy adults is critical to evaluate further the risk and benefit of these drugs and to design treatment strategies to reduce cardiovascular disease risk. (End of Abstract)